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1. (WO2013106646) COMPOUNDS AND METHODS FOR THE INHIBITION OF VCB E3 UBIQUITIN LIGASE
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

Claims:

1. A compound according to the chemical structure:


Where R1 is an optionally substituted Ci-C6 alkyl group, an optionally substituted

-(CH2)nOH, an optionally substituted -(CH2)nSH, an optionally substituted (CH2)n-0-(C1-C6)alkyl group, an optionally substituted (CH2)n-WCOCW-(Co-C6)alkyl group containing an epoxide moiety WCOCW where each W is independently H or a C]-C3 alkyl group, an optionally substituted -(CH2)„COOH, an optionally substituted -(CH2)nC(0)-(Ci-C6 alkyl), an optionally substituted -(CH2)nNHC(0)-Ri, an optionally substituted -(CH2)nC(0)-NR1R2, an optionally substituted

-(CH2)„OC(0)-NRiR2, -(CH20)nH, an optionally substituted -(CH2)nOC(0)-(C1-C6 alkyl), an optionally substituted -(CH2)nC(0)-0-(C1-C6 alkyl), an optionally substituted

-(CH20)nCOOH, an optionally substituted -(OCH2)nO-(Ci-C6 alkyl), an optionally substituted -(CH20)nC(0)-(Ci-C6 alkyl), an optionally substituted -(OCH2)nNHC(0)-Ri, an optionally substituted -(CH20)nC(0)-NRiR2, -(CH2CH20)„H, an optionally substituted

-(CH2CH20)„COOH, an optionally substituted -(OCH2CH2)nO-(C1-C6 alkyl), an optionally substituted -(CH2CH20)nC(0)-(C1-C6 alkyl), an optionally substituted

-(OCH2CH2)nNHC(0)-Ri, an optionally substituted -(CH2CH20)„C(0)-NRiR2,an optionally substituted -S02Rs, an optionally substituted S(0)Rs, N02, CN or halogen (F, CI, Br, I, preferably F or CI);

R\ and R2 are each independently H or a Ci-C6 alkyl group which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine);

Rs is a C!-C6 alkyl group, an optionally substituted aryl, heteroaryl or heterocycle group or a -(C¾)raNRiR2 group,

X and X' are each independently C=0, C=S, -S(0), S(0)2 , (preferably X and X' are both C=0);

R2 is an optionally substituted -(CH2)n-(C=0)u(NRi)v(S02)w(Ci-C6)alkyl group, an optionally substituted -(CH2)n-(C=0)u(NRi)v(S0 )wNR1NR2N group, an optionally substituted -(CH2)n-(C=O)u(NRi)v(S02)w-Aryl, an optionally substituted

-(CH2)n-(C=0)u(NRi)v(S02)w-Heteroaryl, an optionally substituted

-(CH2)n-(C=0)vNRi(S02)w-Heterocycle, an optionally substituted

-NRI-(CH2)n-C(0)u(NRi)v(S02)w-CI-C6 alkyl, an optionally substituted

-NR1-(CH2)n-C(0)u(NR1)v(S02)w- NR1NR2N, an optionally substituted

-NR1-(CH2)n-C(0)u(NRI)v(S02)w-NRiC(0)R1N, an optionally substituted

-NR1-(CH2)n-(C=0)u(NRi)v(S02)w-Aryl, an optionally substituted

-NRI-(CH2)n-(C=0)u(NR1)v(S02)w-Heteroaryl or an optionally substituted

-NR1-(CH2)n-(C=0)vNR1(S02)w-Heterocycle, an optionally substituted

-X -C1-C6 alkyl group; an optionally substituted

-X1 2 - Aryl group; an optionally substituted

-X^2 - Heteroaryl group; an optionally substituted

n '

-X - Heterocycle group; an optionally substituted;

R3 is an optionally substituted Ci-C6 alkyl, an optionally substituted

-(CH2)n-C(0)u(NRi)v(S02)w-Ci-C6 alkyl, an optionally substituted

-(CH2)n-C(0)u(NRi)v(S02)w-NRiNR2N, an optionally substituted

-(CH2)n-C(0)u(NR1)v(S02)w-NR1C(0)R1N, an optionally substituted

-(CH2)n-C(0)u(NRI)v(S02)w-C(O)NR1R2, an optionally substituted

-(CH2)n-C(0)u(NRi)v(S02)w-Aryl, an optionally substituted

-(CH2)n-C(0)u(NRi)v(S02)w-Heteroaryl, an optionally substituted

-(CH2)n-C(0)u(NRi)v(S02)w-Heterocycle, an optionally substituted

-NR1-(CH2)n-C(0)u(NR1)v(S02)w-C1-C6 alkyl, an optionally substituted


NRmR2N, an optionally substituted

- RI-(CH2)n-C(0)u(NR1)v(S02)w- NR!C(0)R1N, an optionally substituted

-NR1-(CH2)n-C(0)u(NR1)v(S02)w-Aryl, an optionally substituted

-NR1-(CH2)n-C(0)u(NR1)v(S02)w-Heteroaryl, an optionally substituted

-NR1-(CH2)n-C(0)u(NRi)v(S02)w-Heterocycle, an optionally substituted

-0-(CH2)n-(C=0)u(NRi)v(S02)w-Ci-C6 alkyl, an optionally substituted

-0-(CH2)n-(C=0)u(NR1)v(S02)w-NRiNR2N, an optionally substituted

-0-(CH2)n-(C=0)u(NRi)v(S02)w-NR1C(0)RIN, an optionally substituted -0-(CH2)n-(C=0)u(NRi)v(S02)w-Aryl, an optionally substituted

-0-(CH2)n-(C=0)u(NRi)v(S02)w-Heteroaryl or an optionally substituted

-0-(CH2)n- (C=0)u(NRi)v(S02)w-Heterocycle;

-(CH2)n-(V)n'-(CH2)n-(V)n'-Ci-C6 alkyl group, an optionally substituted

-(CH2)n-(V)n'-(CH2)n-(V)n'-Aryl group, an optionally substituted

-(CH2)n-(V)n-(CH2)n-(V)n-Heteroaryl group, an optionally substituted

-(CH2)n-(V)n'-(CH2)n-(V)n'-Heterocycle group, an optionally substituted

-(CH2)n-N(R1 (C=O)m-(V)n'-Ci-C6 alkyl group, an optionally substituted

-(CH2)n-N(Ri-)(C=0)m-(V)n-Aryl group, an optionally substituted

-(CH2)n-N(R1')(C=:0)m-(V)n'-Heteroaryl group, an optionally substituted

-(CH2)n-N(Ri >)(C=0)m>-(V)n'-Heterocycle group, an optionally substituted

-XR3 -Ci-C6 alkyl group; an optionally substituted

-XR3 - Aryl group; an optionally substituted

-XR3 - Heteroaryl group; an optionally substituted

-XR3 - Heterocycle group; an optionally substituted;

Where RJN and R2N are each independently H, C]-C6 alkyl which is optionally substituted with one or two hydroxyl groups and up to three halogen groups or an optionally substituted

-(CH2)n-Aryl, -(CH2)n-Heteroaryl or -(CH2)n-Heterocycle group;

V is 0, S or NRi;

Ri is the same as above;

R1 and Rp are each independently H or a C1-C3 alkyl group;

are each independently an optionally substituted -CH2)n-, -CH2)n-CH(XV)=CH(XV)- (cis or trans), -CH2)n-CH≡CH- , -(CH2CH20)n- or a C3-C6 cycloalkyl group, where Xv is H, a halo or a C1-C3 alkyl group which is optionally substituted;

Each m is independently 0, 1 , 2, 3, 4, 5, 6;

Each m' is independently 0 or 1 ;

Each n is independently 0, 1, 2, 3, 4, 5, 6;

Each n' is independently 0 or 1 ;

Each u is independently 0 or 1 ;

Each v is independently 0 or 1 ;

Each w is independently 0 or 1, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

2. The compound according to claim 1 according to the chemical structure:


Wherein each of R1 , R2 and R3 are the same as in claim 1 above and X is C=0, C group or a S(0)2 group, or

A pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

3. The compound according to claim 1 according to the chemical structure:


1 ' 2' 3 '

Where R' , R" and RJ are the same as presented above, or

A pharmaceutically acceptable enantiomer, diastereomer, solvate or polymorph thereof.

4. The compound according to any of claims 1-3 wherein R1 is a hydroxyl group or a group which may be metabolized to a hydroxyl or carboxylic group, such that the compound represents a prodrug form of an active compound.

5. The compound according to any of claims 1-4 wherein R1 is -(CH2)nOH, -(CH2)nSH -(CH2)n-0-(C i -C6)alkyl group, -(CH2)nCOOH, -(CH20)nH, an optionally substituted

-(CH2)nOC(0)-(C C6 alkyl), or an optionally substituted -(CH2)nC(0)-0-(Ci-C6 alkyl), wherein n is 0 or 1.

6. The compound according to any of claims 1-5 wherein X and X', where present, are a C=0, C=S, -S(O) group or a S(0)2 group.

7. The compound according to any of claims 1 -6 wherein X and X' are both C=0 groups.

8. The compound according to any of claims 1 -7 wherein R1 is OH.

9. The compound according to any of claims 1-8 wherein R2 is an optionally substituted -NR'-T-Aryl, an optionally substituted -NR'-T-Heteroaryl group or an optionally substituted -NR'-T-Heterocycle, where R1 is H or CH3, H; and

T is an optionally substituted -(CH2)n- group, wherein each one of the methylene groups may be optionally substituted with one or two substituents, which may be optionally substituted; and n is preferably 0, 1 , 2 or 3, preferably 0 or 1.

10. The compound according to claim 9 wherein said Aryl group is an optionally substituted phenyl or naphthyl group.

11. The compound according to claim 9 wherein said Aryl group is a phenyl group which is optionally substituted with a halogen group, an amine, monoalkyl- or dialkyl amine, OH, SH, CH3> CF3, OMe, OCF3, N02, or CN group, each of which may be substituted in the ortho-, meta- and/or para- positions of the phenyl ring.

12. The compound according to claim 10 wherein said Aryl group is a phenyl group which is optionally substituted with a heteroaryl group.

13. The compound according to claim 12 wherein said heteroaryl group is an optionally substituted isoxazole, an optionally substituted oxazole, an optionally substituted thiazole, an optionally substituted isothiazole, an optionally substituted pyrrole, an optionally substituted imidazole, an optionally substituted oximidazole, an optionally substituted diazole, an optionally substituted triazole group, an optionally substituted pyridine group or an optionallyl substituted oxapyridine group.

14. The compound according to claim 13 wherein said optionally substituted isoxazole is a methylsubstituted isoxazole, said optionally substituted oxazole is a methylsubstituted oxazole, said optionally substituted thiazole is a methyl substituted thiazole, said optionally substituted isothiazole is a methyl substituted isothiazole, said optionally substituted pyrrole is a methylsubstituted pyrrole, said optionally substituted imidazole is a

a methylimidazole, a benzylimidazole or a methoxybenzylimidazole, said optionally substituted oximidazole is a methyloximidazole, said optionally substituted diazole is a methyldiazole, said optionally substituted triazole group is a methylsubstituted triazole group, said optionally substituted pyridine group is a halosubstituted or methylsubstitutedpyridine and said oxapyridine group is linked to the phenyl group by an oxygen.

15. The compound according to claim 9 wherein said Aryl group is a phenyl group which is optionally substituted with a heterocycle selected from the group consisting of piperidine and morpholine.

16. The compound according to claim 9 wherein said Aryl group is a phenyl which is substituted with a methyl-substituted thiazole group.

17. The compound according to claim 9 wherein said Heteroaryl group is an optionally substituted quinoline, an optionally substituted indole, an optionally substituted azaindole, an optionally substituted isoxazole, an optionally substituted thiazole, an optionally substituted isothiazole, an optionally substituted benzofuran, an optionally substituted thiophene or an optionally substituted pyridine.

18. The compound according to claim 17 wherein said isoxazole is a methylsubstituted isoxazole.

19. The compound according to claim 17 wherein said thiophene is a methylsubstituted thiophene.

20. The compound according to claim 17 wherein said 2-, 3-, or 4-pyridine is

methylsubstituted.

21. The compound according to claim 17 wherein said thiazole is a methylsubstituted thiazole.

22. The compound according to claim 9 wherein said Heterocycle is selected from the group consisting of tetrahydroquinoline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, pyrrollidine, morpholine, oxane or thiane, each of which groups is optionally substituted.

23. The compound according to claim 10 wherein said Aryl group is a phenyl group which is optionally substituted with a halogen, an amine, monoalkylamine, dialkylamine, OH, SH, COOH, CH3, CF3, OMe, OCF3, N02, or CN group, an optionally substituted phenyl group, wherein said phenyl group is itself optionally substituted with at least one of F, CI, OH, SH, COOH, CH3, CF3, OMe, OCF3, N02, or CN group, a naphthyl group, which may be optionally substituted, or an optionally substituted heteroaryl or heterocycle group.

24. The compound according to claim 23 wherein said optionally substituted heteroaryl is an optionally substituted isoxazole, an optionally substituted oxazole, an optionally substituted thiazole, an optionally substituted pyrrole, an optionally substituted imidazole, an optionally substituted benzimidazole, an optionally substituted oximidazole an optionally substituted diazole group, including a methyldiazole group, an optionally substituted triazole group, including a methylsubstituted triazole group, an optionally substituted pyridine group, including a halo- (preferably, F) or methylsubstitutedpyridine group or an oxapyridine group, an optionally substituted furan, an optionally substituted benzofuran, an optionally substituted dihydrobenzofuran, an optionally substituted indole, an optionally substituted indolizine, an optionally substitutedazaindolizine, an optionally substituted quinoline, or an optionally substituted group according to the chemical structure:

Where Sc is CHR¾¾, NRUKfc, or O;

RHET is H, CN, N02, halo (preferably CI or F), optionally substituted Ci-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF3), optionally substituted 0(C]-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group -C≡C-Ra where Ra is H or a Q-C6 alkyl group (preferably Ci-C3 alkyl);

Rss is H, CN, N02, halo (preferably F or CI), optionally substituted C C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted 0-(C[-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted -C(0)(Ci-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);

RURE is H, a d-C6 alkyl (preferably H or C C3 alkyl) or a -C(0)(Ci-C6 alkyl) each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine groups, or an optionally substituted phenyl group, an optionally substituted heteroaryl, or an optionally substituted heterocycle, preferably for example piperidine, morpholine, pyrrolidine, tetrahydrofuran);

RPRO is H, optionally substituted -C6 alkyl or an optionally substituted aryl group or an optionally substituted heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine; RPR01 and RPR02 are each independently H, an optionally subsituted C!-C3 alkyl group or together form a keto group and

Each n is independently 0, 1, 2, 3, 4, 5, or 6,

Or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

25. The compound according to claim 23 wherein said optionally substituted heterocycle is selected from the group consisting of pyrollidine, furan, tetrahydrofuran, tetrahydrothiene, piperidine, piperazine and morpholine.

26. The compound according to any of claims 1-25 wherein R3' is an optionally substituted -T-Aryl, an optionally substituted, -T-Heteroaryl, an optionally substituted

-T-Heterocycle, an optionally substituted -NR1 -T-Aryl, an optionally substituted

-NR1 -T-Heteroaryl or an optionally substituted -NR1 -T-Heterocycle; and

T is a -(CH2)n group, -(CH20)n- group, a -(OCH2)n- group, a -(CH2CH20)n- group, or a -(OCH2CH2)n- group, each of which groups is optionally substituted with one or two substituents; and n is 0, 1, 2 or 3.

27. The compound according to claim 26 wherein said Aryl group is an optionally substituted phenyl or naphthyl group.

28. The compound according to claim 27 wherein said Aryl group is a phenyl group which is optionally substituted with a halogen (preferably F or CI), an amine, monoalkyl- or dialkyl amine, an amido group, OH, SH, CH3, CF3, OMe, OCF3, N02, ,CN or a S(0)2Rs group where Rs is a Ci-C6 alkyl group, a -(CH2)mNRiR2 group or an optionally substituted aryl, heteroaryl or heterocycle group, each of which may be substituted in ortho-, meta- and/or para- positions of the phenyl ring, or said phenyl group is optionally substituted with an aryl, heteroaryl or heterocycle, each of which groups is optionally substituted, where m is 0, 1, 2, 3, 4, 5 or 6 and Ri and R2 are each independently H or a Ci-C6 alkyl group which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups.

29. The compound according to claim 28 wherein said Aryl group is a phenyl group which is optionally substituted with a heteroaryl group.

30. The compound according to claim 29 wherein said heteroaryl group is an optionally substituted isoxazole, an optionally substituted oxazole, an optionally substituted thiazole, an optionally substituted pyrrole, an optionally substituted imidazole, an optionally substituted oximidazole, an optionally substituted diazole is a methyldiazole, an optionally substituted triazole group, an optionally substituted pyridine group or an optionallyl substituted oxapyridine group.

31. The compound according to claim 30 wherein said optionally substituted isoxazole is a methylsubstituted isoxazole, said optionally substituted oxazole is a methylsubstituted oxazole, said optionally substituted thiazole a methyl substituted thiazole, said optionally substituted pyrrole is a methylsubstituted pyrrole, said optionally substituted imidazole is a a methylimidazole, a benzylimidazole or a methoxybenzylimidazole, said optionally substituted oximidazole is a methyloximidazole, said optionally substituted diazole is a methyldiazole, said optionally substituted triazole group is a methylsubstituted triazole group, said optionally substituted pyridine group is a halosubstituted or methylsubstitutedpyridine and said oxapyridine group is linked to the phenyl group by an oxygen.

32. The compound according to claim 28 wherein said Aryl group is a phenyl group which is optionally substituted with a heterocycle selected from the group consisting of piperidine and morpholine.

33. The compound according to claim 26 wherein said Heteroaryl group is an optionally substituted quinoline which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring, an optionally substituted indole, an optionally substituted benzimidazole, an optionally substituted benzodiazole, an optionally substituted benzoxofuran, an optionally substituted imidazole, an optionally substituted isoxazole, an optionally substituted oxazole, an optionally substituted diazole, an optionally substituted benzofuran, an optionally substituted thiophene, an optionally substituted thiazole, an optionally substituted triazole, a triisopropylsilyl group, an optionally substituted -(CH2)m-0-Ci-C6 alkyl group, an optionally substituted -(CH2)m-C(0)-0-Ci-C6 alkyl group) or an optionally substituted 2-, 3, or 4-pyridine and m is 0, 1, 2, 3, 4, 5, or 6.

34. The compound according to claim 26 wherein said Heteroaryl group is a methylsubstituted oxazole or a triazole which is optionally substituted with a methyl group, a triisopropylsilyl group, an optionally substituted -(CH2)m-0-Ci-C6 alkyl group or an optionally substituted -(CH2)m-C(0)-0-Ci-C6 alkyl group).

35. The compound according to claim 26 wherein said Heterocycle is selected from the group consisting of tetrahydroquinoline, tetrahydrofuran, tetrahydrothiene, piperidine, piperazine, pyrrolidine and morpholine, each of which groups may be optionally substituted.

36. A compound according to the chemical structure:


Where R1' is OH or a group which can be metabolized in a patient or subject to OH;

R2' is an optionally substituted -NRi-X112 -alkyl group, an optionally substituted -NRi-X 2'- Aryl group; an optionally substituted -NRi- Xs2 -HET group, an optionally substituted -NRi- X^'-Aryl-HET group or an optionally substituted -NRj- X^'-HET-Aryl group,

is H or a C1-C3 alkyl group;

X 2' is an optionally substituted -CH2)n- , -CH2)n-CH(Xv)=CH(Xv)- (cis or trans),

-CH2)n-CH≡CH-, -(CH2CH20)n- or a C3-C6 cycloalkyl group;

R3' is an optionally substituted -(CH2)n-(V)n>-(CH2)n-(V)n'-RS3'group, an optionally substituted -(CH2)n-N(Rr)(C=0)m-(V)n-RS3' group, an optionally substituted -XR3'-alkyl group, an optionally substituted -XR3 -Aryl group; an optionally substituted -XR3 -HET group, an optionally substituted -XR3 -Aryl-HET group or an optionally substituted -XR3 -HET- Aryl group,

RS3 is an optionally substituted Cj-Cio alkyl group, an optionally substituted Aryl group or a HET group;

Ri' is H or a Q-C3 alkyl group;

V is O, S or NRp;

XR3' is an optionally substituted -CH )n- , -CH2)n-CH(Xv)=CH(Xv)- (cis or trans),

-CH2)„-CH≡CH-, -(CH2CH20)n- or a C3-C6 cycloalkyl group;

Xv is H, a halo or a Q-C3 alkyl group which is optionally substituted with one or two hydroxyl groups or up to three halogen groups;

Alkyl is an optionally substituted Ci-C10 alkyl group;

Aryl is an optionally substituted phenyl or naphthyl group; and

HET is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahycirothiene, pyridine, piperidine, piperazine, morpholine, benzofbran, indole, indolizine, azaindolizine, quinoline or a group according to the chemical structure:

Where Sc is CHRSS, NRURE, or O;

RHET is H, CN, N02, halo, optionally substituted Q-C6 alkyl, optionally substituted 0(C!-C6 alkyl) or an optionally substituted acetylenic group -C≡C-Ra where Ra is H or a Ci-C6 alkyl group;

Rss is H, CN, N02, halo, optionally substituted Ci-C6 alkyl, optionally substituted 0-(C]-C6 alkyl) or an optionally substituted -C(0)(C1-C6 alkyl;

RURE is H, a Ci-C6 alkyl or a -C(0)(CrC6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogens, or an optionally substituted heterocycle; and

Yc is N or C-RYC, where RYC is H, OH, CN, N02, halo, optionally substituted Ci-C6 alkyl, optionally substituted 0(Ci-C6 alkyl) or an optionally substituted acetylenic group -C≡C-Ra where Ra is the same as above;

RP 0 is H, optionally substituted Ci-C6 alkyl or an optionally substituted aryl or an optionally substituted heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine;

RPR01 and RPR02 are each independently H, an optionally subsituted C1-C3 alkyl group or together form a keto group,

m' is 0 or 1 ;

Each n is independently 0, 1 , 2, 3, 4, 5, or 6 and

Each n' is independently 0 or 1 , or a

pharmaceutically acceptable salt, stereoisomer, solvent or polymorph thereof.

37. A compound according to the chemical structure:


Where Rr is OH or a group which is metabolized in a patient or subject to OH;

R2' is a -NH-CH2-Aryl-HET;

R3' is a -CHRCR3'-NH-C(0)-R3P1 group or a -CHRCR3'-R3P2 group;

Where RCR3' is a C1-C4 alkyl group;

R3P1 is Q-C3 alkyl group, an optionally substituted oxetane group, a -(CH2)„OCH3 group

where n is 1 or 2, o
CH3CH20-group is linked to phenyl in a meta or para position, or a morpholino group linked to the carbonyl at the 2- or 3-position;

Where Aryl is phenyl;

HET is an optionally substituted thiazole or isothiazole; and

RHET is H or a halo group,

Or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

A compound according to claim 37 according to the chemical structure:

or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

39. A compound of claim 1 as set forth in Affinity Table 2, figure 14, figure 15 or figure 16 hereof.

40. A compound according to claim 1 according to the chemical structure:

259

260

262

263

264


a pharmaceutically acceptable salt thereof.

A compound according to claim 1 according to

267

269

272

Or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

A compound according to claim 1 according to the chemical formula:


Or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

43. A compound according to claim 1 according to the chemical formula:

274

Or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

44. A compound according to claim 1 according to the chemical formula:


Where X is halogen, Q-C3 alkyl or an optionally substituted heterocycle; and

R1 and R2 are each independently H, Ci-C3 alkyl optionally substituted with one or two hydroxyl groups, or an optionally substituted phenyl group, or

A pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.

45. A pharmaceutical composition comprising an effective amount of a compound according to any of claims 1-44 in combination with a pharmaceutically acceptable carrier, additive or excipient and optionally in further combination with a erythropoieses stimulating agent.

46. The composition according to claim 45 wherein said erythropoiesis stimulating agent is EPO or darbapoietin alfa.

47. A method of modulating VCB E3 Ubiquitin Ligase comprising exposing said ligase to a compound according to any of claims 1-44.

48. The method according to claim 47 wherein said modulation occurs in a patient or subject.

49. The method according to claim 47 or 48 wherein said compound is an inhibitor of said ligase.

50. A method of stimulating erythropoiesis in a subject or patient in need comprising administering to said patient an effective amount of a composition according to claim 45 or 46 to said patient.

51. The method according to claim 50 wherein said stimulating increases the red blood cells and/or the hematocrit of said patient or subject.

52. A method of treating anemia in a patient or subject comprising administering to said patient an effective amount of a composition according to claim 45 or 46 to said patient.

53. The method according to claim 52 wherein said anemia is chronic anemia or anemia associated with chronic kidney disease, dialysis and/or cancer chemotherapy.

54. A method of treating ischemia, stroke and/or damage to the cardiovascular system during ischemia in a patient in need comprising administering an effective amount of a composition according to claim 45 or 46 to said patient.

55. A method of enhancing wound healing in a patient in need comprising administering to said patient an effective amount of a composition according to claim 45 or 46 to said patient.

56. A method of reducing scarring secondary to wound healing in a patient in need comprising administering to said patient an effective amount of a composition according to claim 45 or 46 to said patient.

57. A method of enhancing angiogenesis and/or arteriogenesis in a patient in need comprising administering to said patient an effective amount of a composition according to claim 45 or 46.

58. The method according to claim 57 wherein said enhancing of angiogenesis occurs locally in said patient.

59. A method of reducing the likelihood of stent occlusion in a patient in need comprising administering to said patient an effective amount of a composition according to claim 45 or 46 to said patient.

60. Use of a compound according to any of claims 1-44 as a VHL ligand to prepare a bifunctional molecule which links said VHL ligand through a linking group to a protein binding moiety that selectively binds to a target protein and facilitates modulation of levels of said target protein by action of the VHL ligand moiety.

61. Use according to claim 60 wherein said linker is a polyethylene glycol having between 2 and 6 glycol units and the protein binding moiety is an estrogen binding moiety.

62. Use of a compound according to any of claims 1-44 in a first medical application.

63. Use of a compound according to any of claims 1-44 for modulating VCB E3 Ubiquitin Ligase.

64. Use according to claim 63wherein said modulation occurs in a patient or subject.

65. Use according to claim 63 or 64 wherein said compound is an inhibitor of said ligase.

66. Use of a composition according to claim 45 or 46 for stimulating erythropoiesis in a subject or patient in need.

67. Use according to claim 66 wherein said stimulating increases the red blood cells and/or the hematocrit of said patient or subject.

68. Use of a composition according to claim 45 or 46 for treating anemia in a patient or subject.

69. Use according to claim 68 wherein said anemia is chronic anemia or anemia associated with chronic kidney disease, dialysis and/or cancer chemotherapy.

70. Use of a composition according to claim 45 or 46 for treating ischemia, stroke and/or damage to the cardiovascular system during ischemia in a patient in need.

71. Use of a composition according to claim 45 or 46 for enhancing wound healing in a patient.

72. Use of a composition according to claim 45 or 46 for reducing scarring secondary to wound healing in a patient in need.

73. Use of a composition according to claim 45 or 46 for enhancing angiogenesis and/or arteriogenesis in a patient in need.

74. Use according to claim 73 wherein said enhancing of angiogenesis occurs locally in said patient.

75. Use of a composition according to claim 45 or 46 for reducing the likelihood of stent occlusion in a patient in need.